Methods and devices for delivering therapeutic agents to target vessels

ABSTRACT

The present disclosure pertains to stents having a coating applied thereto, wherein the coating comprises a biocompatible polymer/drug mixture, as well as devices comprising a metallic stent, a biocompatible polymeric carrier and a drug.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/792,114, filed Jun. 2, 2010, which is a divisional of U.S.application Ser. No. 12/204,987, filed Sep. 5, 2008 (abandoned), whichis a continuation of U.S. application Ser. No. 11/555,420, filed Nov. 1,2006, now U.S. Pat. No. 7,666,222, which in turn is a continuation ofSer. No. 10/951,385, filed Sep. 28, 2004, now U.S. Pat. No. 7,223,286,which is a continuation of Ser. No. 10/408,328, filed Apr. 7, 2003, nowissued as U.S. Pat. No. 6,808,536, which is a continuation ofapplication Ser. No. 09/874,117, filed Jun. 4, 2001, now issued as U.S.Pat. No. 6,585,764, which is a continuation of application Ser. No.09/061,568, filed Apr. 16, 1998, now issued as U.S. Pat. No. 6,273,913,which in turn claims benefit of provisional application Ser. No.60/044,692, filed Apr. 18, 1997. The disclosures of each of these priorapplications are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

Delivery of rapamycin locally, particularly from an intravascular stent,directly from micropores in the stent body or mixed or bound to apolymer coating applied on stent, to inhibit neointimal tissueproliferation and thereby prevent restenosis. This invention alsofacilitates the performance of the stent in inhibiting restenosis.

BACKGROUND OF THE INVENTION

Re-narrowing (restenosis) of an artherosclerotic coronary artery afterpercutaneous transluminal coronary angioplasty (PTCA) occurs in 10-50%of patients undergoing this procedure and subsequently requires eitherfurther angioplasty or coronary artery bypass graft. While the exacthormonal and cellular processes promoting restenosis are still beingdetermined, our present understanding is that the process of PTCA,besides opening the artherosclerotically obstructed artery, also injuresresident coronary arterial smooth muscle cells (SMC). In response tothis injury, adhering platelets, infiltrating macrophages, leukocytes,or the smooth muscle cells (SMC) themselves release cell derived growthfactors with subsequent proliferation and migration of medial SMCthrough the internal elastic lamina to the area of the vessel intima.Further proliferation and hyperplasia of intimal SMC and, mostsignificantly, production of large amounts of extracellular matrix overa period of 3-6 months results in the filling in and narrowing of thevascular space sufficient to significantly obstruct coronary blood flow.

Several recent experimental approaches to preventing SMC proliferationhave shown promise althrough the mechanisms for most agents employed arestill unclear. Heparin is the best known and characterized agent causinginhibition of SMC proliferation both in vitro and in animal models ofballoon angioplasty-mediated injury. The mechanism of SMC inhibitionwith heparin is still not known but may be due to any or all of thefollowing: 1) reduced expression of the growth regulatory protooncogenesc-fos and c-myc, 2) reduced cellular production of tissue plasminogenactivator; are 3) binding and dequestration of growth regulatory factorssuch as fibrovalent growth factor (FGF).

Other agents which have demonstrated the ability to reduce myointimalthickening in animal models of balloon vascular injury are angiopeptin(a somatostatin analog), calcium channel blockers, angiotensinconverting enzyme inhibitors (captopril, cilazapril), cyclosporin A,trapidil (an antianginal, antiplatelet agent), terbinafine (antifungal),colchicine and taxol (antitubulin antiproliferatives), and c-myc andc-myb antinsense oligonucleotides.

Additionally, a goat antibody to the SMC mitogen platelet derived growthfactor (PDGF) has been shown to be effective in reducing myointimalthickening in a rat model of balloon angioplasty injury, therebyimplicating PDGF directly in the etiology of restenosis. Thus, while notherapy has as yet proven successful clinically in preventing restenosisafter angioplasty, the in vivo experimental success of several agentsknown to inhibit SMC growth suggests that these agents as a class havethe capacity to prevent clinical restenosis and deserve carefulevaluation in humans.

Coronary heart disease is the major cause of death in men over the ageof 40 and in women over the age of fifty in the western world. Mostcoronary artery-related deaths are due to atherosclerosis.Atherosclerotic lesions which limit or obstruct coronary blood flow arethe major cause of ischemic heart disease related mortality and resultin 500,000-600,000 deaths in the United States annually. To arrest thedisease process and prevent the more advanced disease states in whichthe cardiac muscle itself is compromised, direct intervention has beenemployed via percutaneous transiuminal coronary angioplasty (PTCA) orcoronary artery bypass graft (CABG).

PTCA is a procedure in which a small balloon-tipped catheter is passeddown a narrowed coronary artery and then expanded to re-open the artery.It is currently performed in approximately 250,000-300,000 patients eachyear. The major advantage of this therapy is that patients in which theprocedure is successful need not undergo the more invasive surgicalprocedure of coronary artery bypass graft. A major difficulty with PTCAis the problem of post-angioplasty closure of the vessel, bothimmediately after PTCA (acute reocclusion) and in the long term(restenosis).

The mechanism of acute reocclusion appears to involve several factorsand may result from vascular recoil with resultant closure of the arteryand/or deposition of blood platelets along the damaged length of thenewly opened blood vessel followed by formation of a fibrin/red bloodcell thrombus. Recently, intravascular stents have been examined as ameans of preventing acute reclosure after PTCA.

Restenosis (chronic reclosure) after angioplasty is a more gradualprocess than acute reocclusion: 30% of patients with subtotal lesionsand 50% of patients with chronic total lesions will go on to restenosisafter angioplasty. While the exact mechanism for restenosis is stillunder active investigation, the general aspects of the restenosisprocess have been identified.

In the normal arterial will, smooth muscle cells (SMC) proliferate at alow rate (<0.1%/day; ref). SMC in vessel wall exists in a ‘contractile’phenotype characterized by 80-90% of the cell cytoplasmic volumeoccupied with the contractile apparatus. Endoplasmic reticulum, golgibodies, and free ribosomes are few and located in the perinuclearregion. Extracellular matrix surrounds SMC and is rich in heparin-likeglycosylaminoglycans which are believed to be responsible formaintaining SMC in the contractile phenotypic state.

Upon pressure expansion of an intracoronary balloon catheter duringangioplasty, smooth muscle cells within the arterial wall becomeinjured. Cell derived growth factors such as platelet derived growthfactor (PDGF), basic fibroblast growth factor (bFGF), epidermal growthfactor (EGF), etc. released from platelets (i.e., PDGF) adhering to thedamaged arterial luminal surface, invading macrophages and/orleukocytes, or directly from SMC (i.e., BFGF) provoke a proliferationand migratory response in medial SMC. These cells undergo a phenotypicchange from the contractile phenotyope to a ‘synthetic’ phenotypecharacterized by only few contractile filament bundles but extensiverough endoplasmic reticulum, golgi and free ribosomes.Proliferation/migration usually begins within 1-2 days post-injury andpeaks at 2 days in the media, rapidly declining thereafter (Campbell etal., In: Vascular Smooth Muscle Cells in Culture, Campbell, J. H. andCampbell, G. R., Eds, CRC Press, Boca.Ratioh, 1987, pp. 39-55); Clowes,A. W. and Schwartz, S. M., Circ. Res. 56:139-145, 1985).

Finally, daughter synthetic cells migrate to the intimal layer ofarterial smooth muscle and continue to proliferate. Proliferation andmigration continues until the damaged luminal endothelial layerregenerates at which time proliferation ceases within the intima,usually within 7-14 days postinjury. The remaining increase in intimalthickening which occurs over the next 3-6 months is due to an increasein extracellular matrix rather than cell number. Thus, SMC migration andproliferation is an acute response to vessel injury while intimalhyperplasia is a more chronic response. (Liu et al., Circulation,79:1374-1387, 1989).

Patients with symptomatic reocclusion require either repeat PTCA orCABG. Because 30-50% of patients undergoing PTCA will experiencerestenosis, restenosis has clearly limited the success of PTCA as atherapeutic approach to coronary artery disease. Because SMCproliferation and migration are intimately involved with thepathophysiological response to arterial injury, prevention of SMCproliferation and migration represents a target for pharmacologicalintervention in the prevention of restenosis.

SUMMARY OF THE INVENTION

Novel Features and Applications to Stent Technology

Currently, attempts to improve the clinical performance of stents haveinvolved some variation of either applying a coating to the metal,attaching a covering or membrane, or embedding material on the surfacevia ion bombardment. A stent designed to include reservoirs is a newapproach which offers several important advantages over existingtechnologies.

Local Drug Delivery from a Stent to Inhibit Restenosis

In this application, it is desired to deliver a therapeutic agent to thesite of arterial injury. The conventional approach has been toincorporate the therapeutic agent into a polymer material which is thencoated on the stent. The ideal coating material must be able to adherestrongly to the metal stent both before and after expansion, be capableof retaining the drug at a sufficient load level to obtain the requireddose, be able to release the drug in a controlled way over a period ofseveral weeks, and be as thin as possible so as to minimize the increasein profile. In addition, the coating material should not contribute toany adverse response by the body (i.e., should be non-thrombogenic,non-inflammatory, etc.). To date, the ideal coating material has notbeen developed for this application.

An alternative would be to design the stent to contain reservoirs whichcould be loaded with the drug. A coating or membrane of biocompatablematerial could be applied over the reservoirs which would control thediffusion of the drug from the reservoirs to the artery wall.

One advantage of this system is that the properties of the coating canbe optimized for achieving superior biocompatibility and adhesionproperties, without the addition requirement of being able to load andrelease the drug. The size, shape, position, and number of reservoirscan be used to control the amount of drug, and therefore the dosedelivered.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be better understood in connection with the followingfigures in which FIGS. 1 and 1 a are top views and section views of astent containing reservoirs as described in the present invention;

FIGS. 2 a and 2 b are similar views of an alternate embodiment of thestent with open ends;

FIGS. 3 a and 3 b are further alternate figures of a device containing agrooved reservoir; and

FIG. 4 is a layout view of a device containing a reservoir as in FIG. 3.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Pharmacological attempts to prevent restenosis by pharmacologic meanshave thus far been unsuccessful and all involve systemic administrationof the trial agents. Neither aspirin-dipyridamole, ticlopidine, acuteheparin administration, chronic warfarin (6 months) normethylprednisolone have been effective in preventing restenosis althoughplatelet inhibitors have been effective in preventing acute reocclusionafter angioplasty. The calcium antagonists have also been unsuccessfulin preventing restenosis, although they are still under study. Otheragents currently under study include thromboxane inhibitors,prostacyclin mimetics, platelet membrane receptor blockers, thrombininhibitors and angiotensin converting enzyme inhibitors. These agentsmust be given systemically, however, and attainment of a therapeuticallyeffective dose may not be possible; antiproliferative (oranti-restenosis) concentrations may exceed the known toxicconcentrations of these agents so that levels sufficient to producesmooth muscle inhibition may not be reached (Lang et al., 42 Ann. Rev.Med., 127-132 (1991); Popma et al., 84 Circulation, 1426-1436 (1991)).

Additional clinical trials in which the effectiveness for preventingrestenosis of dietary fish oil supplements, thromboxane receptorantagonists, cholesterol lowering agents, and serotonin antagonists hasbeen examined have shown either conflicting or negative results so thatno pharmacological agents are as yet clinically available to preventpost-angioplasty restenosis (Franklin, S. M. and Faxon, D. P., 4Coronary Artery Disease, 2-32-242 (1993); Serruys, P. W. et al., 88Circulation, (part 1) 1588-1601, (1993).

Conversely, stents have proven useful in preventing reducing theproliferation of restenosis. Stents, such as the stent 10 seen in layoutin FIG. 4, balloon-expandable slotted metal tubes (usually but notlimited to stainless steel), which when expanded within the lumen of anangioplastied coronary artery, provide structural support to thearterial wall. This support is helpful in maintaining an open path forblood flow. In two randomized clinical trials, stents were shown toincrease angiographic success after PTCA, increase the stenosed bloodvessel lumen and to reduce the lesion recurrence at 6 months (Serruys etal., 331 New Eng Jour. Med, 495, (1994); Fischman et al., 331 New EngJour. Med, 496-501 (1994). Additionally, in a preliminary trial, heparincoated stents appear to possess the same benefit of reduction instenosis diameter at follow-up as was observed with non-heparin coatedstents. Additionally, heparin coating appears to have the added benefitof producing a reduction in sub-acute thrombosis after stentimplantation (Serruys et al., 93 Circulation, 412-422, (1996). Thus, 1)sustained mechanical expansion of a stenosed coronary artery has beenshown to provide some measure of restenosis prevention, and 2) coatingof stents with heparin has demonstrated both the feasibility and theclinical usefulness of delivering drugs to local, injured tissue off thesurface of the stent.

Numerous agents are being actively studied as antiproliferative agentsfor use in restenosis and have shown some activity in experimentalanimal models. These include: heparin and heparin fragments (Clowes andKarnovsky, 265 Nature, 25-626, (1977); Guyton, J. R. et al. 46 Circ.Res., 625-634, (1980); Clowes, A. W. and Clowes, M. M., 52 Lab. Invest.,611-616, (1985); Clowes, A. W. and Clowes, M. M., 58 Circ. Res., 839-845(1986);. Majesky et al., 61 Circ Res., 296-300, (1987); Snow et al., 137Am. J. Pathol., 313-330 (1990); Okada, T. et al., 25 Neurosurgery,92-898, (1989) colchicine (Currier, J. W. et al., 80 Circulation, 11-66,(1989), taxol (ref), agiotensin converting enzyme (ACE) inhibitors(Powell, J. S. et al., 245 Science, 186-188 (1989), angiopeptin(Lundergan, C. F. et al., 17 Am. J. Cardiol. (Suppi. B); 132B-136B(1991), Cyclosporin A (Jonasson, L. et. al., 85 Proc. Nati, Acad. Sci.,2303 (1988), goat-anti-rabbit PDGF antibody (Ferns, G. A. A., et al.,253 Science, 1129-1132 (1991), terbinafine (Nemecek, G. M. et al., 248J. Pharmacol. Exp. Thera., 1167-11747 (1989), trapidil (Liu, M. W. etal., 81 Circulation, 1089-1093 (1990), interferon-gamma (Hansson, G. K.and Holm, 84 J. Circulation, 1266-1272 (1991), steroids (Colburn, M. D.et al., 15 J. Vasc. Surg., 510-518 (1992), see also Berk, B. C. et al.,17 J. Am. Coll. Cardiol., 111B-1 17B (1991), ionizing radiation (ref),fusion toxins (ref) antisense oligonucleotides (ref), gene vectors(ref), and rapamycin (see below).

Of particular interest in rapamycin. Rapamycin is a macrolide antibioticwhich blocks IL-2-mediated T-cell proliferation and possessesantiinflammatory activity. While the precise mechanism of rapamycin isstill under active investigation, rapamycin has been shown to preventthe G.sub.1 to 5 phase progression of T-cells through the cell cycle byinhibiting specific cell cyclins and cyclin-dependent protein kinases(Siekierka, Immunol. Res. 13: 110-116, 1994). The antiproliferativeaction of rapamycin is not limited to T-cells; Marx et al. (Circ Res76:412-417, 1995) have demonstrated that rapamycin preventsproliferation of both rat and human SMC in vitro while Poon et al. haveshown the rat, porcine, and human SMC migratin can also be inhibited byrapamycin (J Clin Invest 98: 2277-2283, 1996). Thus, rapamycin iscapable of inhibiting both the inflammatory response known to occurafter arterial injury and stent implantation, as well as the SMChyperproliferative response. In fact, the combined effects of rapamycinhave been demonstrated to result in a diminished SMC hyperproliferativeresponse in a rat femoral artery graft model and in both rat and porcinearterial balloon injury models (Gregory et al., Transplantation55:1409-1418, 1993; Gallo et al., in press, (1997)). These observationsclearly support the potential use of rapamycin in the clinical settingof post-angioplasty restenosis.

Although the ideal agent for restenosis has not yet been identified,some desired properties are clear: inhibition of local thrombosiswithout the risk systemic bleeding complications and continuous andprevention of the dequale of arterial injury, including localinflammation and sustained prevention smooth muscle proliferation at thesite of angioplasty without serious systemic complications. Inasmuch asstents prevent at least a portion of the restenosis process, an agentwhich prevents inflammation and the proliferation of SMC combined with astent may provide the most efficacious treatment for post-angioplastyrestenosis.

Experiments

Agents: Rapamycin (sirolimus) structural analogs (macrocyclic lactones)and inhibitors of cell-cycle progression.

Delivery Methods:

These can vary:

-   -   Local delivery of such agents (rapamycin) from the struts of a        stent, from a stent graft, grafts, stent cover or sheath.    -   Involving comixture with polymers (both degradable and        nondegrading) to hold the drug to the stent or graft.    -   or entrapping the drug into the metal of the stent or graft body        which has been modified to contain micropores or channels, as        will be explained further herein.    -   or including covalent binding of the drug to the stent via        solution chemistry techniques (such as via the Carmeda process)        or dry chemistry techniques (e.g. vapour deposition methods such        as rf-plasma polymerization) and combinations thereof.    -   Catheter delivery intravascularly from a tandem balloon or a        porous balloon for intramural uptake.    -   Extravascular delivery by the pericardial route.    -   Extravascular delivery by the advential application of sustained        release formulations.

Uses:

-   -   for inhibition of cell proliferation to prevent neointimal        proliferation and restenosis.    -   prevention of tumor expansion from stents.    -   prevent ingrowth of tissue into catheters and shunts inducing        their failure.        1. Experimental Stent Delivery Method—Delivery from Polymer        Matrix:

Solution of Rapamycin, prepared in a solvent miscible with polymercarrier solution, is mixed with solution of polymer at finalconcentration range 0.001 weight % to 30 weight % of drug. Polymers arebiocompatible (i.e., not elicit any negative tissue reaction or promotemural thrombus formation) and degradable, such as lactone-basedpolyesters or copolyesters, e.g., polylactide,polycaprolacton-glycolide, polyorthoesters, polyanhydrides; poly-aminoacids; polysaccharides; polyphosphazenes; poly(ether-ester) copolymers,e.g., PEO-PLLA, or blends thereof. Nonabsorbable biocompatible polymersare also suitable candidates. Polymers such as polydimethylsiolxane;poly(ethylene-vingylacetate); acrylate based polymers or copolymers,e.g., poly(hydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone;fluorinated polymers such as polytetrafluoroethylene; cellulose esters.

Polymer/drug mixture is applied to the surfaces of the stent by eitherdip-coating, or spray coating, or brush coating or dip/spin coating orcombinations thereof, and the solvent allowed to evaporate to leave afilm with entrapped rapamycin.

2. Experimental Stent Delivery Method—Delivery from Microporous Depotsin Stent Through a Polymer Membrane Coating:

Stent, whose body has been modified to contain micropores or channels isdipped into a solution of Rapamycin, range 0.001 wt % to saturated, inorganic solvent such as acetone or methylene chloride, for sufficienttime to allow solution to permeate into the pores. (The dipping solutioncan also be compressed to improve the loading efficiency.) After solventhas been allowed to evaporate, the stent is dipped briefly in freshsolvent to remove excess surface bound drug. A solution of polymer,chosen from any identified in the first experimental method, is appliedto the stent as detailed above. This outer layer of polymer will act asdiffusion-controller for release of drug.

3. Experimental Stent Delivery Method—Delivery via Lysis of a CovalentDrug Tether:

Rapamycin is modified to contain a hydrolytically or enzymaticallylabile covalent bond for attaching to the surface of the stent whichitself has been chemically derivatized to allow covalent immobilization.Covalent bonds such as ester, amides or anhydrides may be suitable forthis.

4. Experimental Method--Pericardial Delivery:

A: Polymeric Sheet

Rapamycin is combined at concentration range previously highlighted,with a degradable polymer such as poly(caprolactone-gylcolid-e) ornon-degradable polymer, e.g., polydimethylsiloxane, and mixture cast asa thin sheet, thickness range 10.mu. to 1000.mu. The resulting sheet canbe wrapped perivascularly on the target vessel. Preference would be forthe absorbable polymer.

B: Conformal Coating:

Rapamycin is combined with a polymer that has a melting temperature justabove 37° C., range 40°-45° C. Mixture is applied in a molten state tothe external side of the target vessel. Upon cooling to body temperaturethe mixture solidifies conformably to the vessel wall. Bothnon-degradable and absorbable biocompatible polymers are suitable.

As seen in the figures it is also possible to modify currentlymanufactured stents in order to adequately provide the drug dosages suchas rapamycin. As seen in FIGS. 1 a, 2 a and 3 a, any stent strut 10, 20,30 can be modified to have a certain reservoir or channel 11, 21, 31.Each of these reservoirs can be open or closed as desired. Thesereservoirs can hold the drug to be delivered. FIG. 4 shows a stent 40with a reservoir 45 created at the apex of a flexible strut. Of course,this reservoir 45 is intended to be useful to deliver rapamycin or anyother drug at a specific point of flexibility of the stent. Accordingly,this concept can be useful for “second generation” type stents.

In any of the foregoing devices, however, it is useful to have the drugdosage applied with enough specificity and enough concentration toprovide an effective dosage in the lesion area. In this regard, thereservoir size in the stent struts must be kept at a size of about0.0005″ to about 0.003″. Then, it should be possible to adequately applythe drug dosage at the desired location and in the desired amount.

These and other concepts will are disclosed herein. It would be apparentto the reader that modifications are possible to the stent or the drugdosage applied. In any event, however, the any obvious modificationsshould be perceived to fall within the scope of the invention which isto be realized from the attached claims and their equivalents.

What is claimed:
 1. A stent having a coating applied thereto, whereinsaid coating comprises a biocompatible polymer/drug mixture, saidpolymer is a nonabsorbable polymer, and said drug is rapamycin and iscontained in the coating in weight percentage of about 30%.
 2. The stentaccording to claim 1 comprising a generally thin walled cylindercontaining a plurality of generally solid struts to which said coatingis applied.
 3. The stent according to claim 2 further comprising achannel formed in at least one of said struts.
 4. The stent according toclaim 3, wherein said channel has a closed perimeter on all sides, anopen top and a generally rectangular perimeter, and said channel issmaller in all dimensions than said strut.
 5. The stent according toclaim 1 wherein the coating is dip-coated onto the stent.
 6. The stentaccording to claim 1 wherein the coating is spray-coated onto the stent.7. The stent according to claim 1 wherein the coating comprises apolydimethylsiloxane; a poly(ethylene)vinylacetate; apoly(hydroxy)ethylmethylmethacrylate; an acrylate based polymer; anacrylate based copolymer; a polyvinyl pyrrolidone; a cellulose ester; afluorinated polymer; or a blend thereof.
 8. The stent according to claim7 wherein the coating comprises a fluorinated polymer.
 9. The stentaccording to claim 1 that provides a controlled release of saidrapamycin over a period of several weeks.
 10. The stent according toclaim 1 wherein said rapamycin is present in a therapeuticallybeneficial amount to inhibit neointimal proliferation.
 11. A devicecomprising a metallic stent, a biocompatible polymeric carrier and adrug that are present in a weight ratio of about 7:3, wherein saidpolymer is a nonabsorbable polymer, said drug is rapamycin and ispresent in an amount effective to inhibit neointimal proliferation. 12.The device according to claim 11 wherein said polymeric carrier and drugare mixed together.
 13. The device according to claim 11 wherein saidpolymeric carrier is bound to the drug.
 14. The device according toclaim 11 wherein the drug is entrapped on the surface of the stent bysaid polymeric carrier.
 15. The device according to claim 11 whereinsaid stent comprises a generally thin walled cylinder containing aplurality of generally solid struts to which said polymeric carrier anddrug are applied.
 16. The device according to claim 15 furthercomprising a channel formed in at least one of said struts.
 17. Thedevice according to claim 16, wherein said channel has a closedperimeter on all sides, an open top and a generally rectangularperimeter, and said channel is smaller in all dimensions than saidstrut.
 18. The device according to claim 11 wherein the polymericcarrier and drug are dip-coated onto the stent.
 19. The device accordingto claim 11 wherein the polymeric carrier and drug are spray-coated ontothe stent.
 20. The device according to claim 11 wherein the polymericcarrier comprises a polydimethylsiloxane; a poly(ethylene)vinylacetate;a poly(hydroxy)ethylmethylmethacrylate; an acrylate based polymer; anacrylate based copolymer; a polyvinyl pyrrolidone; a cellulose ester; afluorinated polymer; or a blend thereof.
 21. The device according toclaim 11 wherein the polymeric carrier comprises a fluorinated polymer.22. The device according to claim 11 that provides a controlled releaseof said rapamycin over a period of several weeks.